The poor regenerative ability of axons in the adult mammalian central nervous system (CNS) underlies the limited functional recovery following spinal cord injury, traumatic brain injury, white matter stroke and certain neurodegenerative disorders. There are two forms of injury-induced axonal growth that may contribute to functional repair: regeneration of injured axons and compensatory growth (or sprouting) of uninjured axons. The goal of this application is to gain a better understanding of the role of the molecular players - both extrinsic factors in the CNS environment and intrinsic factors in the neurons - in axon sprouting and regeneration. The study will focus on two inhibitors of axon growth made by the CNS myelin (Nogo, OMgp) and PTEN, a negative regulator of neuron-intrinsic growth potential. The overall approach is to study the responses of axons to injury in mice lacking one or more growth regulators so the normal function of these proteins can be assessed. Aim 1 will determine the cell type that is important for the role of Nogo in axon sprouting of the corticospinal tract (CST), whether Nogo and OMgp synergize to prevent CST axon sprouting, and will further explore the functional consequences of such enhanced sprouting in conjunction with rehabilitation. Aim 2 will determine the combined effect of targeting the myelin inhibitor(s) and PTEN on spinal axon sprouting and regeneration, and whether enhanced axonal growth leads to synapse formation and functional recovery. The proposal takes advantage of the power of mouse genetics to pinpoint the role of specific intrinsic and extrinsic regulators and will likely yield important insights on the functions of these molecules in injury-induced axonal growth. A better understanding of the molecular determinants of injury-induced axonal growth in the adult CNS is crucial to the design of effective therapeutic strategies for various neurological conditions including spinal cord injury. PUBLIC HEALTH RELEVANCE: The proposed study will provide important insight on the role of myelin inhibitors and PTEN in spinal axon regeneration and sprouting. Understanding the role of these extrinsic and intrinsic regulators of axonal repair is crucial to the design of effective therapeutic intervention to promote CNS repair following brain and spinal cord injury, stroke and related neurological conditions.